Metastatis of cancer to bone is the leading cause of pain in patients with malignant tumors. Such pain is intense and unremitting, and results in severe limitation of activity and a drastic decrease in quality of life. Opiates are the most common treatment for pain management in cancer patients reporting moderate to severe pain. The chronic nature of cancer pain often requires prolonged treatment with opiates. In naive animals, sustained opiate exposure induces unexpected neuroplastic adaptations that paradoxically enhance pain. Opioid-induced hyperalgesia may potentially exacerbate some aspects of cancer pain. Little is known about the consequences of sustained opiate administration on bone cancer-induced pain, bone destruction, phenotypic changes in primary afferent nociceptive fibers and spinal cord, and disease progression. This proposal uses a murine bone cancer model in which sarcoma cells are injected and sealed into the femur, resulting in anatomical localization of the tumor. This allows for analysis of the effects of sustained opiates on tumor growth and progression, changes in bone morphology, cancer-induced pain, and phenotypic characteristics in the dorsal root ganglia (DRG) and spinal cord under closely controlled conditions. This proposal tests the hypothesis that sustained opiate administration enhances sarcoma-induced pain, alters the phenotypic characteristics of the DRG and spinal cord of sarcoma mice differentially from mice with sarcoma alone or opiate exposure alone, enhances tumor growth, and enhances bone destruction (Aim 1) in a time- and dosedependent manner (Aim 2) through a mu opioid receptor specific mechanism (Aim 3). Our goal is to obtain sufficient preliminary data to allow detailed characterization of mechanisms of opiate-induced adverse actions in cancer pain which would be explored in a subsequent RO1 application. Such increases in our understanding could help identify treatment options limiting the potentially deleterious actions of opiates, and changing the way these drugs are used to treat cancer-induced pain.